presidential symposium epilepsy care: a futurist view · 2016. 11. 29. · presidential symposium...
TRANSCRIPT
Presidential Symposium Epilepsy Care: A Futurist View
Symposium Chair:
Michael Privitera, M.D.
Saturday, December 3, 2016 Convention Center – General Assembly
8:30 – 11:45 a.m.
Accreditation The American Epilepsy Society is accreditedby the Accreditation Council for ContinuingMedical Education (ACCME) to providecontinuing medical education for physicians.
AMA Credit Designation StatementThe American Epilepsy Society designates this live activity for amaximum of 29.50 AMA PRA Category 1 Credits™. Physiciansshould claim only the credit commensurate with the extent oftheir participation in the activity.
International Credits: The American Medical Association hasdetermined that non-U.S. licensed physicians who participate inthis CME activity are eligible for a maximum of 29.50 AMA PRACategory 1 Credits™.
Physician Assistants: AAPA accepts certificates of participationfor educational activities certified for AMA PRA Category 1Credits™ from organizations accredited by ACCME or arecognized state medical society. Physician assistants mayreceive a maximum of 29.50 hours of Category 1 credit forcompleting this program.
Continuing Education for Nurses andPharmacists
Jointly provided by AKH, Inc.,Advancing Knowledge in Healthcare,and the American Epilepsy Society.
Nurses:Advancing Knowledge in Healthcare is accredited as aprovider of continuing nursing education by the AmericanNurses Credentialing Center’s Commission on Accreditation.This activity is awarded 29.50 contact hours.
Pharmacists:Advancing Knowledge inHealthcare is accredited by the AccreditationCouncil for Pharmacy Education as a provider ofcontinuing pharmacy education.
Select portions of this Annual Meeting are approved forpharmacy CE credit. Specific hours of credit for approvedpresentations and the Universal Activity Numbers assigned tothose presentations are found elsewhere in the programmaterials. Criteria for success: credit is based on documentedprogram attendance and online completion of a programevaluation/assessment.
If you have any questions about this CE activity relative tonursing and/or pharmacy CE, please contact AKH Inc [email protected].
The American Board of Psychiatry and Neurology has reviewedthe 70th Annual Meeting — American Epilepsy Society and hasapproved this program as part of a comprehensive epilpesyprogram, which is mandated by the ABMS as a necessarycomponent of maintenance of certification.
Claiming CME Credit and CME CertificatesAttendees who registered in the following categories may claimCME or CE for the meeting: physician, health care provider,trainee, one-day and two-day. Meeting registration includescredit claiming: there is no separate fee to claim CME/CE.
Attendees will receive an emailed notification to access theonline evaluation and credit claim system.
The evaluation and credit claim system will remain openthrough Tuesday, February 28, 2017. Evaluations and creditclaims must be completed by this date in order to record andreceive your CME/CE certificate.
Attendance Certificate/International AttendeesA meeting attendance certificate will be available at theregistration desk for international meeting attendees onTuesday, December 6.
Resolution of Conflicts of InterestIt is the policy of the American Epilepsy Society to ensurebalance, independence, objectivity and scientific rigor. Allpersons involved in the selection, development andpresentation of content are required to disclose any real orapparent conflicts of interest. In accordance with the ACCMEStandards for Commercial Support of CME, AES implementedthe mechanism of prospective peer review of this CME activity,to identify and resolve any conflicts. Additionally, the content ofthis activity is based on the best available evidence.
Unapproved Use DisclosureAES requires CME authors to disclose to learners whenproducts or procedures being discussed are off-label,unlabeled, experimental and/or investigational (not FDAapproved); and any limitations on the information that ispresented, such as data that are preliminary or that representongoing research, interim analyses and/or unsupportedopinion. This information is intended solely for continuingmedical education and is not intended to promote off-label useof these medications. If you have questions, contact themedical affairs department of the manufacturer for the mostrecent prescribing information. Information aboutpharmaceutical agents/devices that is outside of U.S. Food andDrug Administration approved labeling may be contained inthis activity.
DisclaimerThis CME activity is for educational purposes only and does notconstitute the opinion or endorsement of, or promotion by, theAmerican Epilepsy Society. Reasonable efforts have been takento present educational subject matter in a balanced, unbiasedfashion and in compliance with regulatory requirements.However, each activity participant must always use his or herown personal and professional judgment when consideringfurther application of this information, particularly as it mayrelate to patient diagnostic or treatment decisions including,without limitation, FDA-approved uses and any off-label,investigational and/or experimental uses.
EDUCATION CREDITS
American Epilepsy Society | www.AESnet.org | Houston, Texas 70th Annual Meeting | 6th Biennial North American Regional Epilepsy Congress 23
OVERVIEW This session will begin by outlining the current state of epilepsy diagnosis and treatment, then identify existing roadblocks and speculate on future trends. Key topics for the current and future management of epilepsy will include: 1) existing, new and future approaches to epilepsy surgery and devices; 2) development of new antiepileptic and antiepileptogenic medications; 3) how understanding molecular mechanisms in signaling pathways like mTOR, and new and future gene discoveries will influence diagnosis and treatment; 4) how the expanding field of bioinformatics will influence decision making now and in the future; and 5) how current and future brain imaging methods will be applied to epilepsy. LEARNING OBJECTIVES Following participation in this symposium, learners should be able to: • List several molecular pathways that may be altered in people with epilepsy and identify existing
treatment(s) that can be applied. • Describe the process for the development of new antiepileptic drugs. • Delineate the risks and benefits of the currently available surgical approaches to treating people with
epilepsy. • Employ bioinformatic methods to create performance improvement projects with existing clinical data. • Select the appropriate currently available bioimaging technique(s) to optimize diagnosis and treatment for
people with epilepsy. • Describe how current and future brain imaging methods can supplement and enhance neuropsychological
evaluation and outcomes. TARGET AUDIENCE Intermediate: Epilepsy fellows, epileptologists, epilepsy neurosurgeons, and other providers with experience in epilepsy care (e.g., advanced practice nurses, nurses, physician assistants), neuropsychologists, psychiatrists, basic and translational researchers. Advanced: Address highly technical or complex topics (e.g., neurophysiology, advanced imaging techniques or advanced treatment modalities, including surgery.) PROGRAM Chair: Michael Privitera, M.D. Introduction Michael Privitera, M.D. Current and Future Approaches to Surgery and Devices for Epilepsy Dennis Spencer, M.D. (Change in order from Program Book) Harnessing the Power of Bioinformatics in Epilepsy Tracy Glauser, M.D. Brain Imaging in Epilepsy Now and in the Future Jerzy Szaflarski, M.D., Ph.D. Current and Future Trends in Development of Antiepileptic Drugs Henrik Klitgaard, Ph.D. Genes and Signaling Pathways: Future Therapeutic Strategies Peter Crino, M.D., Ph.D., The Fritz R. Dreifuss Lecture
Conclusions Michael Privitera, M.D. Education Credit 2.5 CME Credits Nurses may claim up to 2.5 contact hours for this session.
Pharmacy Credit Pharmacists: AKH Inc., Advancing Knowledge in Healthcare approves this knowledge-based activity for 2.5 contact hours (0.25 CEUs). UAN 0077-9999-16-085-L01-P. Initial Release Date: 12/3/16.
COMMERCIAL SUPPORT ACKNOWLEDGEMENT Supported in part by educational grants from Eisai Inc., Lundbeck, UCB, Inc., and Sunovion Pharmaceuticals Inc. FACULTY/PLANNER DISCLOSURES It is the policy of the AES to make disclosures of financial relationships of faculty, planners and staff involved in the development of educational content transparent to learners. All faculty participating in continuing medical education activities are expected to disclose to the program audience (1) any real or apparent conflict(s) of interest related to the content of their presentation and (2) discussions of unlabeled or unapproved uses of drugs or medical devices. AES carefully reviews reported conflicts of interest (COI) and resolves those conflicts by having an independent reviewer from the Council on Education validate the content of all presentations for fair balance, scientific objectivity, and the absence of commercial bias. The American Epilepsy Society adheres to the ACCME’s Essential Areas and Elements regarding industry support of continuing medical education; disclosure by faculty of commercial relationships, if any, and discussions of unlabeled or unapproved uses will be made. FACULTY / PLANNER BIO AND DISCLOSURES Michael D. Privitera, MD, Chair Professor, Director Epilepsy Center University of Cincinnati Gardner Neuroscience Institute Dr. Michael Privitera is Professor of Neurology and Director of the Epilepsy Center at the University of Cincinnati Gardner Neuroscience Institute. He established the Epilepsy Center in Cincinnati in 1987. Dr. Privitera is an expert on advanced treatments for epilepsy, with a research focus on new antiepileptic drugs, generic equivalence of AEDs, and stress as a seizure precipitant. He has over 150 scientific publications. He has mentored dozens of residents, fellows, graduate students and post-docs. He has served as a reviewer for NIH and FDA, earned many honors and awards, and served in many leadership positions at the University of Cincinnati and at the American Epilepsy Society. He is currently President of the American Epilepsy Society. Dr. Privitera discloses receiving support for Consulting Fees (e.g., advisory boards): astellas, Upsher-Smith Laboratories; Contracted Research: GW Pharma, SAGE Therapeutics, UCB Pharma Peter Crino, MD, PhD, Faculty Chairman University of Maryland Peter B. Crino M.D., Ph.D. – brief bio Dr. Crino is Professor and Chair in the Department of Neurology at the University of Maryland School of Medicine. He completed his M.D. at Yale University and Ph.D. at Boston University. He completed neurology residency and post-doctoral fellowship training at the University of Pennsylvania. Dr. Crino is a clinician-scientist
whose research focuses on mechanisms of abnormal brain development associated with the mTOR signaling pathway. Clinically, he is an epileptologist who specializes in tuberous sclerosis complex and related neurodevelopmental disorders associated with epilepsy, autism, and intellectual disability. Dr. Crino discloses receiving support for Consulting Fees (e.g., advisory boards): Evogen Inc.; Royalties: Evogen Inc.; Stockholder/Ownership Interest (excluding diversified mutual funds): Evogen Inc. Tracy A. Glauser, MD, Faculty Director, Comprehensive Epilepsy Program Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. Tracy A. Glauser, MD, is Professor of Pediatrics and Neurology and Director, Comprehensive Epilepsy Center at Cincinnati Children’s Hospital. Dr. Glauser received his medical degree, cum laude, from Jefferson Medical College. He completed his pediatrics residency at Johns Hopkins Hospital, his child neurology fellowship at The Children’s Hospital of Philadelphia, and his epilepsy/electroencephalography fellowship at Washington University School of Medicine. His research focuses on genetic/nonheritable factors that underlie inter-individual variation in AED response. He directed the Childhood Absence Epilepsy trial and received the AES Epilepsy Research Recognition Award for Clinical Science. His fields of expertise are pediatric epilepsy, clinical trials/pharmacology, and pharmacogenetics. Dr. Glauser discloses receiving support for Consulting Fees (e.g., advisory boards): AssureX Health, Supernus; Intellectual Property / Patents: AssureX Health; Royalties: AssureX Health Henrik Klitgaard, PhD, Faculty Vice President, Fellow Neurosciences Therapeutic Area UCB H. Klitgaard, PhD, VP, Fellow in New Medicines UCB, Braine-l’Alleud, BE. PhD in Human Physiology in 1989 at the August Krogh Institute (University of Copenhagen, Denmark). His Post-Doctoral work was partly performed at the Pasteur Institute in France and Harvard University in US. During the last 3O years, he has worked with discovery and development of antiepileptic drugs in the pharmaceutical industry. Member of the Scientific Advisory Committee for CURE (Citizens United for Research in Epilepsy) and the Steering Committee for the Anticonvulsant Screening Program at the National Institutes of Health (NIH). During his career, Dr. Klitgaard has been involved in the discovery and development of several antiepileptic drugs at both Novo Nordisk A/S and at UCB, including tiagabine, levetiracetam and brivaracetam. Dr. Klitgaard discloses receiving support for Salary: UCB Pharma; Stockholder/Ownership Interest (excluding diversified mutual funds): UCB Pharma Dennis D. Spencer, MD, Faculty Physician/Surgeon Yale School of Medicine Dr. Spencer is the Harvey and Kate Cushing Professor of the Department of Neurosurgery at Yale University School of Medicine. He is a graduate of Washington University School of Medicine and completed his neurosurgical residency at Yale in 1977. He joined the Yale neurosurgery faculty following his residency, and became Chief of neurosurgery in 1987. He has an international reputation in the surgical treatment of neurological diseases causing epilepsy and developed a widely used neocortical sparing surgical approach for patients with temporal lobe epilepsy. His research has brought together basic scientists and clinicians around a program concerning energetics, glutamate metabolism and the neurobiological study of human epileptogenic tissue. Study techniques include 7T MRS, C13 intraoperative glucose turnover studies, and in vivo and in vitro electrophysiology and
microdialysis, immunohistochemistry, confocal and EM microscopy, and molecular biology. In particular, laboratory discoveries are correlated with the epileptogenic substrate in order to help define human epilepsy pathogenesis and potential therapies. Dr. Spencer was recipient of the 1999 American Epilepsy Society’s Research Award in Clinical Investigation, and the 2006 Society of Neurological Surgeons’ Grass Award for Excellence in Research. He is past Chairman of the American Board of Neurological Surgery, past President of the Society of Neurological Surgeons, and he served as interim dean of the Yale School of Medicine 2003-2004. He is past Vice Chairman of the Neurosurgery Residency Review Committee for Neurosurgery, and past President of the American Epilepsy Society. Dr. Spencer discloses receiving support for Consulting Fees (e.g., advisory boards): Monteris, Inc. Jerzy Szaflarski, MD, PhD, Faculty Professor and Director, UAB Epilepsy Center University of Alabama at Birmingham Jerzy P. Szaflarski, MD, PhD is Professor of Neurology and Director of the UAB Epilepsy Center. After finishing medical school, he worked in the laboratory of Dr. Faye Silverstein at the University of Michigan where he examined molecular responses to ischemic and NMDA-mediated brain injury. He later completed epilepsy training at the University of Cincinnati with Dr. Michael Privitera, and trained in fMRI with Dr. Jeff Binder at the MCW. As part of K23 training, he spent time in the laboratory of Dr. Jean Gotman at MNI learning EEG/fMRI. For almost 20 years he has been examining the effects of brain injury on brain plasticity using MRI, fMRI, DTI and EEG/fMRI. One of his long-term goals is to develop fMRI as a diagnostic tool for various neurological conditions including epilepsy and as a biomarker for treatment response. Dr. Szaflarski discloses receiving support for Honoraria: GW Pharmaceuticals, Inc, Upsher-Smith Laboratories CME REVIEWERS Suchitra Joshi, MD, MS, Reviewer University of Virginia Dr. Sucheta Joshi, MD, MS, FAAP, FAES (Clinical Associate Professor, Pediatric Neurology, University of Michigan) is a Pediatric Epileptologist. She is the Director of Pediatric Telemedicine Services and Associate Residency Program Director. Her interests include pediatric epilepsy, EEG monitoring and improving access to epilepsy care. She is PI for a HRSA funded project to increase access and quality care for epilepsy in Michigan using a learning collaborative and telemedicine. She is Medical Director for the Coordinating Center of the AAP for Children and Youth with Epilepsy, site co-investigator for the Pediatric Epilepsy Research Consortium, and was part of the EEG core for the EPGP study. She serves as faculty for the AAP and CNS, and has published several peer-reviewed manuscripts and book chapters. Dr. Joshi discloses he has no financial relationships to disclose relevant to this activity. Kinshuk Sahaya, MD, Reviewer Dr. Kinshuk Sahaya is an assistant professor in the Department of Neurology and epileptologist at the University of Arkansas for Medical Sciences (UAMS). He is also the Neurology Resiency Program director at UAMS. He completed his medical school training followed by post-doc research in neuropharmacology at the University College of Medical Sciences (UCMS), University of Delhi, India. His Neurology residency was at the University of Missouri-Columbia and fellowships in clinical neurophysiology & epilepsy at the University of Michigan- Ann Arbor.
His clinical and research interests include eduation, clinical epilepsy, EEG, translational research in epilepsy and pre-surgical evaluation of epilepsy patients. He is actively involved in both resident and medical student education. Dr. Sahaya discloses he has no financial relationships to disclose relevant to this activity. PHARMACY/NURSE PLANNERS Gigi Smith, PhD, RN, CPNP-PC: No financial relationships to disclose relevant to this activity. Dorothy Duffy, PharmD: No financial relationships to disclose relevant to this activity. AKH STAFF / AES STAFF AKH staff and planners: No financial relationships to disclose relevant to this activity. AES staff and planners: No financial relationships to disclose relevant to this activity. CLAIMING CREDIT: PHYSICIANS Attendees who registered in the following categories may claim CME or CE for the meeting: physician, health care provider, trainee, one-day and two-day. Meeting registration includes credit claiming: there is no separate fee to claim CME/CE. Attendees will receive an emailed notification to access the online evaluation and credit claim system. The evaluation and credit claim system will remain open through Tuesday, February 28, 2017. Evaluations and credit claims must be completed by this date in order to record and receive your CME/CE certificate. Physicians can claim CME credit online at https://cme.experientevent.com/AES151/ This Link is NOT Mobile-friendly! You must access it from a laptop, desktop or tablet. How to Claim CME Credit To claim CME credits online, please follow the on-screen instructions at the above url. Log in using your last name and zip code, OR your last name and country if you’re not from the United States. All CME credits must be claimed by February 28, 2017. Questions? Contact Experient Customer Service at: 800-974-9769 or [email protected] NURSING & PHARMACY PLEASE NOTE: Providing your NABP e-profile # is required. The National Association of Boards of Pharmacy (NABP) requires that all pharmacists and pharmacy technicians seeking CE credit have an ID number issued by NABP. Pharmacy CE providers, such as AKH Inc., Advancing Knowledge in Healthcare, are required to submit participant completion information directly to NABP with your ID number and birth information to include month and date (not year) as a validation to this ID number. If you do not have an ID number (this is not your license #), go to: www.MyCPEmonitor.net
Nursing and Pharmacy credit (per session) is based on attendance as well as completion of an online evaluation form available at: WWW.AKHCME.COM/2015AES THIS MUST BE DONE BY JANUARY 15, 2017 TO RECEIVE YOUR CE CREDIT.
We cannot submit credit to NABP after this date. If you have any questions, please contact AKH at [email protected].
DISCLAIMER Opinions expressed with regard to unapproved uses of products are solely those of the faculty and are not endorsed by the American Epilepsy Society or any manufacturers of pharmaceuticals.
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Epilepsy Care: A Futurist View
Michael Privitera, MDUniversity of Cincinnati, Gardner Neuroscience
Institute
Disclosure
UCB‐research GW Pharma‐researchSAGE Therapeutics‐research
Astellas‐DSMBUpsher Smith‐DSMB
• Each speaker will briefly review key aspects of the current state of their assigned area, including current “roadblocks”, then speculate about the future.
• It is not the goal to predict what will happen in the future, but rather use expertise and foresight to describe what could happen in the future and, perhaps, what should happen in the future.
• Can categorize as “residual” as in the ones everyone learned some time ago, “dominant” as in the ones the leaders and advanced thinkers are pushing forward with some data, and “emergent” as in the ones that are more “cutting edge” and may or may not become “dominant” in the future.
Instructions to Speakers: Not Easy!
In 1963, they thought we’d be flying around by now…but they did predict Skype
Electronic tiresShape shifting, self driving, maybe hydrogen powe
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Each pod is a separate “car” that can be re‐arranged
Unclear how it’s powered, but looks really cool
Uber predicts flying commuters in 10 years
Specially designed for Neurologists…
Neurologists are always practical…
#AES2016
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Current and Future Approaches to Surgery and Devices for Epilepsy
Dennis Spencer, M.D.
Yale University
School of Medicine
Disclosure
Name of Commercial Interest
Monteris, Inc.
Type of Relationship
Consulting
Disclosures
• NIH
• Monteris Medical advisory board
Surgical therapies for epilepsyPresent and Future
• The quest for surgical control
• The evolution from focus to network nodes
• Evidence from our surgical patients
• Implications for our present state
• The era of devices
• What we need to move forward
John Hughlings JacksonThe Focus
“There was in every case of epileptiform seizures a persisting discharging lesion whether tumor or not”
“There is very often a dreamy state in cases of this group of epileptic fits, the uncinate group”
Spencer and Ferrier’s stimulation studiesLed him to hypothesize that these seizures started in the uncinate region causing smells and epigastric sensations and then spread to the medulla to cause respiratory arrest rather than starting in the medulla , the conventional wisdom.
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Defining a focus and surgical treatment in Temporal Lobe Epilepsy
• Penfield and Baldwin: 1952, report ECOG
• Resection anteromedial to vein of Labbe
• Niemeyer: selective resection
• Murray Falconer at Guy’s Maudsley:
Denis Hill, epileptologist, surgery advocate
Ben Dawson, devised en bloc resection
1955 30 patients from the psychiatric unit
with 50% control and better psychologically
Murray Falconer
The Key ‐ En Bloc Pathology
• 1963 ‐ team approach bears fruit
• Meyer, Cavanagh, Corsellis, and Bruton
• 100 patients ‐ 53% control, 30% improved
• MTS defined ‐ in 47%, 24% tumors, MCD
• David Taylor: psychosocial and cortical dysplasia, results more than seizure frequency
• Talairach: 1958 depth electrodes interictally
Brazier MAB, Crandall PH, Brown WJ: Long‐term follow up of EEG changes following therapeutic surgery in epilepsy
EEG and Clinical Neurophysiology 38: 495‐506, 1975
• Authors record the stories of 82 patients through the 1960’s
• Ictal recordings the rule since 1970• Discharges all medial• Correlated with MTS in 65%, describes fields• No neocortical envolvement
St. Hilaire JM, Bouvier G, Lymburner J, Picard R, Mercier M. Synchronized Stereoelectroencephalography with Visual and Sound Recording in the Chronic Exploration of Epilepsy. In: L’Union Medicale du Canada. 1976: 1538‐1541.
Temporal Lobe Cortical Resection
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Surgical approaches to the medial temporal lobe
• Selective amygdalohippocampectomy
– Transsylvian
– Transcortical
– Subtemporal
• Electrocorticography (ECoG) guided resection
• Anteromedial resection
• Radiofrequency ablation
• Gamma knife radiosurgery (GKS)
• Emerging therapies
– Endoscopic approaches
– Laser thermocoagulation
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Anteromedial resection
• Recent meta‐analysis shows anteromedial resection to be superior to selective amygdalohippocampectomy for seizure control (Josephson et al.; Neurology 2013)
• Effectiveness of the surgery has been recently scrutinized in relation to neuropsych outcomes as larger resections tend to have worse outcomes for verbal and spatial memory
• Temporal lobe epilepsy surgery and the quest for optimal extent of resection: A review—Johannes Schramm. His review found no clear evidence to support one methodology for seizure control and neuropsychology data are hard to generalize
Lobectomy vs. Selective Resection:Seizure Outcomes
• Retrospective review comparing long term seizure outcomes in 30 patients undergoing temporal lobe resection vs. 39 patients undergoing amygdalohippocampectomy, all with MTS
– Patients undergoing temporal lobe resections demonstrated more durable Engel Class IA when compared to selective resections however all other comparisons demonstrated equivalence
Time to loss of Engel I or II Time to loss of Engel I Time to loss of Engel IA
Bujarski KA, et al., Journal of Neurosurgery. 2013; 119:116‐23
0%
10%
20%
30%
40%
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1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
MTS Neocortical
Extratemporal resectionDisconnections
Neuromodulation• Extratemporal resections• MCD,Normal MRI,Injury• Children: Engel 1‐34%, 2‐15%, 3‐25%, 4‐26%• Adults:• Disconnections: Corpus Callosotomy‐atonic seizures• Hemispherotomy‐Engel 1‐80‐90%• Multiple subpial transections‐E1‐30• Neuromodulation: Vagal nerve stimulation• Responsive direct stimulation• both show 50% decreased frequency• in 50% of patients
Current Surgical Decision tree
Non-invasive workup (including EEG, PET, MRI, fMRI and Neuropsychology)
+/- WADA
Unilobar lesion(tumor or cavernoma) w/ fullconcordance of preop w/u
MTS Cortical dysplasia,diffuse or multifocal lesion,
normal MRI or any discordance of preop w/u
Intracranial EEG
resection/ablation
functional cortex
not involved
functional cortex
involved
HC fxn preserved
HC fxn notpreserved
TemporalLobectomy vs.Laser Ablation
Lesionectomy Functional mapping
Guided resection/ablation vs. RNS
RNS vs. ?Laser Ablation Unifocal Onset Mulitfocal Onset
Fxnl cortex not involved
Fxnl cortex involved
RNS
RNSDBSVNS
• Emerging Concept of Network Epileptogenesis—Clinical Evidence
• Emerging from the 90’s• Rethinking concept of focal epileptogenesis• Epilepsy more of a distributed disorder because:
• 1) Variable ictal onset in the local MTLE circuit
• 2) Seizures sometimes cured by removing one of the local nodes
• 3) 15‐29% of auras persist after AMTL
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The medial temporal lobe network
• Variable contribution from both hippocampus and entorhinal cortex by subdural and depth electrode analysis
• Therefore, focused ablation to include hippocampus exclusively is likely leaving a significant epileptic substrate behind
Spencer SS & Spencer DD, Epilepsia. 1994; 35(4):721‐7
• Emerging Concept of Network Epileptogenesis—Clinical Evidence
• Emerging from the 90’s• Rethinking concept of focal epileptogenesis• Epilepsy more of a distributed disorder because:
• 1) Variable ictal onset in the local MTLE circuit
• 2) Seizures sometimes cured by removing one of the local nodes
• 3) 15‐29% of auras persist after AMTL
Laser Ablation: Where are we now?
• Emory’s experience with 49 laser ablations, including 6 reoperations:– Trajectory targets pes hippocampus
and extends posteriorly to include hippocampus at tectal plate
• Ablation extends anteriorly into the amygdala along this trajectory
– Seizure outcomes: 67% of MTS patients seizure free at 1 year, 50% of non‐MTS patients seizure free at 1 year
• Accounting for provoked seizures, 30% (2/7) had no seizures at 2 years
– Neuropsych results suggest improved object naming and recognition when compared to standard resection
Gross RE, et al., Neurosurg Clin N Am. 2016 27:37–50; Drane DL, et al., Epilepsia. 2015 56(1):101‐13
Seizure Outcomes & Safety
• Meta‐analysis of 350 studies of temporal lobectomy including 25,144 cases*– Engel Class I: 72%
– Engel Class II: 16%
– Engel Class III: 9%
– Engel Class IV: 7%
• 36% Complication rate including 26% with quadrantanopsia
• 68 cases of hippocampal ablation with 6‐12 month follow‐up– Engel Class I: 61%
– Engel Class II: 5%
– Engel Class III: 30%
– Engel Class IV: 15%
• 19% complication including 11% with quadrantanopsia
Attiah MA, et al. Epilepsy Research. 2015, 115:1‐7
*Duration of follow‐up not specified
Post‐Op MR Imaging (2 weeks)* Amygdalar ablation
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• Emerging Concept of Network Epileptogenesis—Clinical Evidence
• Emerging from the 90’s• Rethinking concept of focal epileptogenesis• Epilepsy more of a distributed disorder because:
• 1) Variable ictal onset in the local MTLE circuit
• 2) Seizures sometimes cured by removing one of the local nodes
• 3) 15‐29% of auras persist after AMTL
• 4) Bitemporal epilepsy cured by removing the most dysfunctional hippocampus
• 5) Failure of complete control of MTLE after resection over time
• 6) Difficulty defining epileptogenic regions in neocortical epilepsy
• 7) Distributed deficits in cognitive function by neuropsych testing
• 8) Paradoxical MTLE
• 9) Dual pathology
Hirsch and SpencerBitemporal lobe epilepsy
• 4) Bitemporal epilepsy cured by removing the most dysfunctional hippocampus
• 5) Failure of complete control of MTLE after resection over time
• 6) Difficulty defining epileptogenic regions in neocortical epilepsy
• 7) Distributed deficits in cognitive function by neuropsych testing
• 8) Paradoxical MTLE
• 9) Dual pathology
Long term outcomes in Epilepsy Surgery
• 4) Bitemporal epilepsy cured by removing the most dysfunctional hippocampus
• 5) Failure of complete control of MTLE after resection over time
• 6) Difficulty defining epileptogenic regions in neocortical epilepsy
• 7) Distributed deficits in cognitive function by neuropsych testing
• 8) Paradoxical MTLE
• 9) Dual pathology
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Paradoxical Medial Temporal Lobe epilepsy
• 4) Bitemporal epilepsy cured by removing the most dysfunctional hippocampus
• 5) Failure of complete control of MTLE after resection over time
• 6) Difficulty defining epileptogenic regions in neocortical epilepsy
• 7) Distributed deficits in cognitive function by neuropsych testing
• 8) Paradoxical MTLE
• 9) Dual pathology
Dual Pathology Importance of Seizure freedom
• Seizure freedom by far the most important predictor of post‐surgery QoL
• QoL improvement is 5‐fold lower if seizures only improve but do not cease
• Cognitive decline correlates with worsening of QoL only if seizures don’t improve
WHERE WE ARE
• Three decades of looking for a better sword
• Outcomes have plateaued
• Should be looking at the substrate differently
• Network epileptogenesis
• Laser ablation will be a beneficial tool
• Gold standard will still be intracranial studies
• And human tissue correlative pathology0
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This extensive electrode coverage has identified three common functional networks that may be usurped by the epileptogenic process
Occipital‐Temporal‐Frontal
Frontal ‐Temporal
Frontal –Parietal
Thus when a patient presents with an MRI negative or subtle MRI findings of MCD and noninvasive findings suggestive of a particular lobe the functional network of that lobe is studied with combined surface and depth electrodes
There three common study paradigms
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Seizure onset simultaneous in lateral grid‐19,18 and subtemporal/occipital strip. Onset 3mm from previous depth electrode but was not seen then.Somelanguage in grid but most robust in the strip. Recommended RNS
Research evidence for Epilepsy Networks
Spencer Probe‐ version 2 & Microdialysis Apparatus
Microdialysis CMA/20 probe:• 0.67 mm x 70 mm probe• 10 mm, 20 kDa cut-off membrane
Microdialysis probe inserted into the depth electrode
Depth electrode with perforationsb/w contacts 1 &2 (Ad-Tech)
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Basal Glutamate in Cortex and Hippocampus
Romanyshyn, Cavus et al in prep
NAA Depleted Regions & Overlap w/ EEG Arrays
Single patient MRSI NAA/Cr map of deviation from N=20
normal controls
Overlay of patient’s p-map on the 3D aMRI: intracranial electrode
localization (IcEEG) superimposed
IcEEG positions concordant with significant depletion in N=10 patients
Rigid + nonrigid registration performed to fuse aMRI/EEG/MRSI
data
Voxel Selection and Reconstruction Hippocampus
Voxel Selection and Reconstruction Thalamus and Putamen
Anterior#4-#6
Posterior#1-#3
Network Correlations
Thalamus
Hippocampus
Contra Ipsi
0.58<0.003
0.46<0.03
0.57<0.004
0.48<0.02
0.51<0.01
0.53<0.01
0.76<0.00002
Putamen
The Language of Networks Where are we
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EXPANDING OUR WINDOW TO THE BRAIN
•
Increasing utilization of sophisticated “Bioelectric intracranial integrated devices” to study the “Network Epilepsy Syndromes”
Expansion of intracranial therapeutics-electrical and molecular through feedback loops.
Limitations of intracranial EEG monitoringInfectionPatient mobilityMass of wiresSignal to noise ratioModalities, sensor size, spatial sampling
Solution Strategy
Modality– Measure macro and local field potentials
– Improve spatial sampling and brain coverage-thin films
– Perform multi-modal brain sensing -modalities of interest include EEG, temperature, oxygen, pH, ionic current, neurotransmitters, drugs and metabolites
– Transmit data wirelessly
Solution StrategyMaterials
– Use thin-films
– Decrease mass and volume of electrode contacts, sheathing, and wires
– Devise materials which conform better to complex cortical geometry
– Develop coatings to decrease the foreign body response of the brain
3.1 NeuroProbe: Multimodal Brain Monitoring in the Neuro‐ICU*
Team: Mark Reed, Dennis Spencer, Hitten Zaveri, Emily Gilmore, Jason Gerrard, Nihal de Lanerolle, James Goodrich, Jung Kim
Aim:
• Replace multiple devices with a single device to measure icP, CBF*, icT*, icO*, icEEG for TBI
• Obtain regulatory approval
• Perform studies in rat and swine prior to human use
*Funded by the Connecticut Bioscience Innovation Fund (CBIF)
3.6 Types of Electrodes
Spencer depth electrode
Subdural grid electrode
Subdural strip electrode
NeuroGrid (Buzaki)
UtahElectrodeArray
New generation of electrodes
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2.1 Wireless Intracranial EEG 2.1 Wireless Intracranial EEG
Development funded through NIH SBIR awards to ITN Energy Systems (Littleton, CO) and Yale University
NIH SBIR Phase 1 Effort:• 4 channel wireless intracranial EEG device1
• Powered by RF• Employs IR for data and control communication• Can electrically stimulate from any channel
NIH SBIR Phase 2 Effort:• 64 channel wireless intracranial EEG device2,3
• Can be powered by battery, RF, or wired power• Employs IR for data and control communication• Multiple 64 channel devices can be used to achieve
larger channel counts
1 US Patent 8165684, 20122 US Patent 8738139, 20143 US Patent pending
Aim: To develop a cooling, stimulating and sensing array (CSSA) for human use. This will be a brain implantable device.
Team:1. Yale University (Neurology, Neurosurgery)2. ITN Energy Systems (Littleton, CO)3. UNC Charlotte (Charlotte, NC)4. RTI International (RTP, NC)
2.3 Cooling, Stimulating and Sensing Array (CSSA) 2.3 Focal Cooling ‐ Rodent Test
Rodent Device Test: Assess rodent brain response to focal cooling• Device with two cooling elements (1x2
mm) in contact with cortex.• Cooling elements are embedded
within a device containing a heat sink exposed to the air.
• Cool a focal cortical area• Measure cortical temperature
2.3 Focal Cooling ‐ Human Test
Human Prototype Device Test: Assess human brain response to focal cooling• Device with single cooling element (5x4
mm), embedded within a silastic sheet (30x30 mm)
• Cool a focal cortical area exposed during epilepsy surgery
• Measure temperature and intracranial EEG from multiple points
ConclusionEra of Device Integration with the
Brain
• Goal is targeted therapy of the “Epilepsy Network Syndromes”
• Billions spent on pharmaceuticals ,primarily revisions of older drugs discovered empirically
• We have no idea what to target• When we understand the electrochemical milieu of the epilepsy patient then we may be able to direct therapy
• Therapy for the whole patient not just the seizures
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Harnessing the Power of Bioinformatics in Epilepsy
Tracy Glauser, M.D.
Director, Comprehensive Epilepsy Center
Cincinnati Children’s Hospital Medical Center
Disclosure
AssureX Health – royalties, consulting
Claritas ‐ consulting
Department of Justice – expert witness
Supernus ‐ consulting
Learning Objectives
• Recognize the residual and dominant bioinformaticinnovations that can enhance epilepsy clinical care by improving data and information availability.
• Recognize the emergent bioinformatic innovations that can enhance epilepsy clinical care by increasing knowledge and eventually wisdom.
Translational Medicine and Bioinformatics Continuum
Sarkar: Biomedical informatics and translational medicine. Journal of Translational Medicine 2010 8:22.
Basic science, applications, and bioinformatics
Payne et al. BMC Medical Informatics and Decision Making 2013, 13:20
Biomedical Informatics – the Journey from Data to Wisdom
Information
UnderstandingRelationships
Knowledge
WisdomConnectedness
Understandingpatterns
Understandingprinciples
DataAckoff, R.L. From Data to Wisdom, Journal of Applied System Analysis, 16:3‐9, 1989
RelationalDatabases
KnowledgeBases
Understanding
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Residual Innovations
Need for Human + Information Technology- Clinical decision support systems- Universal electronic health records- Tools for database linkage, mining, and use
“…to accommodate the reality that although professional judgment will always be vital to shaping care, the amount of information required for any given decision is moving beyond unassisted human capacity.”
Institute of Medicine (IOM). 2007. page 5, The Learning Healthcare System: Workshop Summary
Residual Innovations – Electronic Health Records
Scope - Epic is the EHR for healthcare systems serving
54% of all US patients
2.5% of all patients in the world
Glaze, Jeff "Epic Systems draws on literature greats for its next expansion". Wisconsin State Journal.
Residual Innovations – tools for database mining
Collects medical record data for querying and distributionDiscovery on enterprise wide scaleGoal: Cohort identification
DataRepository
(CRC)
FileRepository
IdentityManagement
OntologyManagement
CorrelationAnalysis
De ‐Identification
Of data
NaturalLanguageProcessing
AnnotatingGenomicData #1
ProjectManagement
WorkflowFramework
PFTProcessing
AnnotatingGenomicData #2
AnnotatingImagingData
I2b2 ‐ Informatics for Integrating Biology and the Bedside
Dominant Innovation ‐ National Patient‐Centered Clinical Research Network (PCORnet)
Vision: Enable large-scale clinical research conducted with enhanced quality and efficiency.Mission: Enable faster, more trustworthy clinical research that helps people make informed health decisions
Strategy/Tactics: Create infrastructure, tools, and policies to support rapid, efficient clinical researchUtilize multiple electronic health records, insurance claims data, data reported directly by people, and other data sourcesEngage people, clinicians, and health system leaders throughout the nation
Dominant Innovation ‐ PCORnet results to date20 Patient-Powered Research Networks (PPRNs)
including the Rare Epilepsy Network13: Clinical Data Research Networks (CDRNs)People with data available in PCORnet to date: ~110 Million
*Based on data from 64 DataMarts as of April 22, 2016Development of a common data model:
Procedures
Demographic
Condition
Prescribing
Encounters
Lab Results
Patient Satisfaction
Claims
Biospecimen& Genomic
Data
Vital Status
Rare Epilepsy Network (https://ren.rti.org/)
Dominant Innovations – enhancing patient involvementWearable tech (including home diagnostics)Digital therapeutics (gamification wellness)Health Learning SystemsAugmented Reality/Virtual reality
http://www.dailymail.co.uk/health/article‐3704918/Epilepsy‐spotted‐suit‐tunes‐brain‐worn‐home‐everyday‐clothes.html;http://www.akiliinteractive.com/; https://www.magicleap.com/#/home; http://www.dezeen.com/2014/03/14/epilepsy‐aid‐uses‐wearable‐technology‐to‐predict‐seizures/
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Emergent – Integration of Biomedical Informatics with Epilepsy
• At CCHMC, collaboration between epileptologists and computer scientists started 2003
• Accomplishments:
– Created machine learning infrastructure: epilepsy feature selection, ontology development, classifier construction across 3 children’s hospitals
– Automated optimization: automated method for feature optimization, annotation, data extraction, similarity measurement, physician notification
– Translation to epilepsy clinical care (4 examples):
• Created epilepsy clinical decision support (CHRISTINE system)
• Methodological advances: NLP, spreading activation, machine learning
– Early identification of epilepsy surgery candidates – MD language
– Determine clinical trial participant eligibility – MD language
– Epilepsy co‐morbidity ‐ “Language of suicide” – patient language
Multi‐Center machine learning infrastructure
Selecting anti‐epileptic drugs: a pediatric epileptologist’s view, a computer’s view. Pestian, Matykiewicz, Holland‐Bouley, Standridge, Spencer, and Glauser. Acta Neurol Scand. 2013 March ; 127(3): 208–215
Feature Selection
Ontology ‐ Integrated the International League Against Epilepsy’s (ILAE’s) 1989 and 2010 terminology and concepts with NINDS’s Common Data Elements (CDE)
MiPeds consortium (R01LM011180) ‐ CCHMC, CHOP, Colorado Children’s
Automated annotation ‐ teach Automated annotation ‐ improve
Automated optimization Automated similarity measurements
Similarities between hospitals demonstrated in two ways: number of filled boxes and color of the filled boxes
Green - probability of similarity is between 50% and 100%Yellow - probability of similarity is between 5% and 50%Red - probability of similarity is below 5%.
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Bioinformatics and epilepsy clinical care –Epilepsy decision support (CHRISTINE system)
Bioinformatics and epilepsy clinical care –Epilepsy Surgery Candidate Identification
e e eee ee
ee
ee
Year 1
Year 10Year 6Year 4
Patient Encounter With Neurologist (e)
Bioinformatics and epilepsy clinical care –Epilepsy Surgery Candidate Identification
• Put in production June 2016
• Every Sunday SAM looks for new
candidates
• To date, four new epilepsy surgery
patients identified
• Sends a message to Epilepsy
Surgery Program and the patient’s
attending neurologist
• One R21 (AHRQ - HS024977)
examining optimal method to notify
clinicians about potential epilepsy
surgery candidatesBiomed Inform Insights. 2016 May 22;8:11-8
Bioinformatics and epilepsy clinical care –Clinical Trial Participant Eligibility
Structured Unstructured Structured & Unstructured Precision Sensitivity Specificity Precision Sensitivity Specificity Precision Sensitivity Specificity
Proof of concept study 1 Carbonic anhy-drase inhibitors
0.73 0.48 0.87 0.68 0.65 0.77 0.88 0.30 0.97
Carboxamides 0.77 0.56 0.92 0.56 0.78 0.69 0.89 0.44 0.97
Valproic Acid 0.8 0.27 0.91 0.87 0.9 0.82 ≈1 0.23 ≈1
Succinimides 0.91 0.91 0.98 0.89 0.73 0.98 ≈1 0.64 ≈1
Generalized Epilepsy
0.81 0.61 0.85 0.89 0.86 0.89 0.94 0.57 0.96
Localization related epilepsy
0.64 0.58 0.75 0.83 0.79 0.875 0.86 0.5 0.94
Undetermined Epilepsy Type
0.41 0.63 0.54 0.64 0.37 0.89 0.67 0.21 0.95
Proof of concept study 2 Clinical Trial Simulation
0.67 0.5 0.89 0.69 0.69 0.86 0.88 0.31 0.97
Study 1: 60 patients with epilepsy (average visits = 7). An epileptologist validated the classifiers’ results.Study 2: Review of 60 patients with epilepsy for possible enrollment in a typical epilepsy investigational AED trial. Inclusion criteria: children with localization related epilepsy currently receiving either valproic acid or a carboxamide(carbamazepine or oxcarbazepine). Exclusion criteria: diagnosis of generalized epilepsy or undetermined epilepsy type or absence of valproic acid or carboxamide use.
Suicide – a national issue
• In 2010, 38,364 people in the United States died by suicide.
• About every 13.7 minutes someone in this country intentionally ends his/her life.
• Age
– 10 to 24 Third leading cause of death
– 25 to 34 Second leading cause of death
– 18 to 65 Fourth leading cause of death
www.cdc.gov, MMWR March 2015
Anxiety, Depression, Suicidality How do you make the diagnosis?
• Linguistics, Acoustics, Facial/body expressions are markers of a person’s thoughts
– thought markers Tm• Measuring thought markers is challenging
• Not the same as other biological markers (DNA)
What do people say?
How do they say it?
What is their body language?
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Spreading Activation ‐Mathematical Embodiment
Processing text with domain‐specific spreading activation methods issued 2015 CCHMC US Patent No. 8,930,178
Repeated Suicide Attempts
• Multi‐center study to validate algorithm– Video, audio, linguistic features – Genetic features– In the ED and 30 days later (prediction phase)
• Unique in size and type– N=375– Princeton Community Hospital, Cincinnati Children’s Hospital, University of Cincinnati
• Goal: separate suicidal versus other mental health issues versus controls
Impact on Clinical Care and Practice
• Residual (EHR, database mining tools) and dominant (wearable tech, gamification, health learning systems and augmented and virtual reality) innovations can enhance epilepsy clinical care by improving data and information availability.
• However emergent innovations can transform epilepsy clinical care by increasing knowledge and eventually improving wisdom.
#AES2016
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Page 1
Brain Imaging in EpilepsyNew and into the Future
Jerzy P. Szaflarski, MD, PhDUniversity of Alabama at Birmingham and
UAB Epilepsy Center, Birmingham AL
Page 2
Disclosure
Funding: NIH, Department of Defense, FDA, AES, EFA, NSF, UCB Biosciences, Epilepsy Study Consortium, Shor Foundation for Epilepsy Research, Neuroscan Compumedics Inc., SAGE Therapeutics Inc., GW Pharmaceuticals, and Eisai, Inc.
Consulting/Advisory Boards: Serina Therapeutics, SAGE Therapeutics Inc., Biomedical Systems Inc., GW Pharmaceuticals Inc., NeuroPace, Inc., Upsher-Smith Laboratories, Inc., AL State Medical Board, and Elite Medical Experts LLC.
Editorial board membership: Epilepsy & Behavior, Journal of Epileptology, Restorative Neurology and Neuroscience, Journal of Medical Science, Epilepsy Currents, and Folia Medica Copernicana.
Page 3
Learning Objectives
• Briefly discuss the history of neuroimaging
• Review current state of knowledge regarding MRI in epilepsy
• Discuss future directions and where the future may take us
Page 4
http://my.dmci.net/~casey/experiments.htmMemory and Brain, by Larry R. Squire ISBN-0-19-504208-5Picture circa 1962
Page 5
25 years ago…
Churchland and Sejnowski, 1988, Science
Levels of organization
- CNS- Systems- Maps- Networks- Neurons- Synapses- Molecules
Page 6
Today: Neuroimaging In Epilepsy EEG and MEG
Interictal and Ictal SPECT
TMS
MRI
Structural MRI
Functional MRI
EEG and fMRI (EEG/fMRI)
PET and MRI (PET/MRI)
Multimodality Image Fusion
Now:
Levels of organization
- CNS- Systems- Maps- Networks- Neurons- Synapses- Molecules
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Page 7
Initial structural MRI
Three main circumstances requiring MRI:
Any patient with new onset seizures
Any patient who has long-standing seizures and who has not been properly evaluated
Presurgical evaluation
From Kuzniecky and Jackson “Imaging in Epilepsies” - AT2 weighted image from a 0.5T scanner at MNI showing hippocampal sclerosis - 1986
Page 8
MRI in new onset epilepsy
177/764 had potentially epileptogenic lesion (23%)
28% in patients with an epileptic seizure
53% of patients with focal onset seizures
8% in patients who had non-epileptic event
Lesion types (standard or TLE protocols):
Gliosis or encephalomalacia – 49%
Tumor – 15%
Cavernoma – 9%
MTS 9%
165/764 had non-epileptogenic lesion (22%)
Hakami et al., 2013, Neurology
Page 9
MRI and seizure outcomes
Semah et al., 1998, Neurology
• 2200 adults with epilepsies with 1-7 years follow-up
Page 10
New onset seizure guideline (AAN 2015)
Seizure related to brain lesion – 2-fold higher risk of seizure recurrence when compared to patients with seizures of “unknown cause” (MRI(-))
Krumholz et al., 2015, Neurology
Page 11
AEDs: Diminishing returns
Kwan and Brodie NEJM 2000
TRE = Time to consider epilepsy surgery evaluation
Page 12
MRI findings: Normal vs. Abnormal TLE – 50-80% seizure-free outcome
Presence of HS typically predicts favorable outcome in univariate analyses
May not be an independent predictor in multivariate analyses
E-TLE - seizure-free rates are typically lower in extratemporal neocortical epilepsies
FLE – 13-80%
Presence of extra-frontal abnormality or HS predicted poor outcome
OLE – 46%
TLE w/lesion – 2.5 times higher chance of seizure freedom
E-TLE w/lesion – 2.7 times higher chance of seizure freedom
Jeha et al., 2007 Brain, Salanova et al., 1992 Brain, Tellez-Zenteno et al., 2010 Epilepsy Research
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Page 13
Negative MRI – what next?
What when MRI is “negative”?
Special MRI techniques
High-field / high-resolution
MRS
Special MRI processing techniques
MAP
Page 14
High-field / High-resolution 3T HR-MICRA scan 7T SPACE
Images courtesy of Larry Ver Hoef, MD; UAB
Page 15
HR-MICRA R TLE
Images courtesy of Larry Ver Hoef, MD; UAB Page 16
3T vs. 7T anatomical imaging
Images courtesy of Dr. Jullie Pan, MD, PhD
Page 17
7T MR Spectroscopy
Images courtesy of Dr. Jullie Pan, MD, PhD
Page 18
Morphometric Analysis Program (MAP)
MAP implemented and used in 2005
150 MRI negative patients identified retrospectively (all received surgery prior to MAP)
43% detection rate (sensitivity 0.9 / specificity 0.67)
Resection of entire MAP-identified brain region resulted in significantly improved outcome (p < 0.001)
Huppertz et al., 2005 Epilepsy Research Wang et al., 2015, Annals of Neurology
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Page 19
3T 3D-FLAIR3T T1w
7T T1w 7T T2*GRE
The MAP difference
Images courtesy of Irene Wang, MD; CCF Page 20
Structural MRI Summary - What is missing?
Structural MRI is widely available and a must in patients with epilepsy but
Many patients with TRE are “MRI(-)”
New MRI techniques
Higher resolution / higher SNR
New data processing strategies
Typically small, retrospective analyses are available
Needed are prospective studies evaluating emerging techniques and analysis methods
Page 21
Functional MRI
FMRI is gradually becoming the study of choice for function mapping in the presurgical evaluation
Main areas of use include Imaging of language lateralization and localization
Mapping of memory
Mapping of motor cortex
Localization of interictal epileptiform discharges (EEG/fMRI)
fMRI vs. IAP
Page 22
IAP and fMRI –Not as simple as replacing old with new
Page 23
IAP vs. fMRI – A paradigm shift
Page 24
IAP vs. fMRI
IAP (“gold standard”)
Standard procedure
Invasive
5% risk of complications
Lateralization no localization
Potential for false lateralization
fMRI
New(er) procedure
Non-invasive
0% risk of complications
Lateralization andlocalization
Potential for false lateralization
Data analysis issues i.e. “now you see it, now you don’t”
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Page 25
Semantic Decision/Tone Decision (SD/TD)
Active Condition
hear “horse“ Respond “YES” (button push) if animal is found in the U.S. and is used by people.
Control Condition
hear Respond “YES” (button push) if tone train contains 2 "high" tones.
Page 26
What is BOLD signal?Active condition
Control condition
L=L
Page 27
Correlation between fMRI and IAP
0%
0%
0%
0%
44%
20%
10%
8%
8%
12%a
17%
17%
11%b
5%
24%c
0%
12%
11%d
29%e
29%f
9%
0 10 20 30 40 50 60 70 80 90 100
Woermann et al. 2003
Benke et al. 2006
Arora et al. 2009
Szaflarski et al. 2008
Gaillard et al. 2004
Binder et al. 1996
Spreer et al. 2002
Sabbah et al. 2003
Adcock et al. 2003
Rutten et al. 2002
Gaillard et al. 2002
Deblaere et al. 2004
Yetkin et al. 1998
Benson et al. 1999
Lehericy et al. 2000
Carpentier et al. 2001
Worthington et al. 1997
Baciu et al. 2001
Bahn et al. 1997
Desmond et al. 1995
Hertz-Pannier et al. 1997
Liegeois et al. 2002
Sample Size
Concordance
Discordance
0%
Janacek et al., 2013 Epilepsia Page 28
Discordance between fMRI and IAP
Discordance in ~15% of patients (32/229)
What predicts discordance?
No variable predict discordance
Except when you are atypical on one test you may be more likely to be atypical on the other
Not clear when discordant which one is correct
Janacek et al., 2013 Epilepsia
Page 29
ATL patients with discordant IAP and fMRI
Janacek et al., 2013 Epilepsy & Behavior Page 30
Memory task – Scene encoding
Bigras et al., 2013 EB, Binder et al., 2010 Epilepsia, Mechanic-Hamilton et al., 2009 EB, Rabin et al., 2004 Brain
Active Condition
See: Memorize picture and decide whether this is an indoor (“YES”button push) or outdoor (“NO” button push) scene
See:
Decide whether figures are same or different
Control Condition
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Page 31
Scene encoding 200 patients with TLE (91 L) included
Typically memory activation lateralized to the contralateral (healthy) side
Weak and variable correlation with IAP results
Strong correlation with NP measures
Poor correlation with long-term outcomes
SD/TD better than scene encoding for verbal memory outcome prediction
Bigras et al., 2013 EB, Binder et al., 2010 Epilepsia, Mechanic-Hamilton et al., 2009 EB, Rabin et al., 2004 Brain Page 32
Predictors of Naming Decline in Left ATL
FMRI LI:
Wada Language LI:
Pre-operative BNT Score:
Age at Seizure Onset:
R p
-.64 <.001
-.50 <.05
-.40 n.s.
-.35 n.s.
FMRI: 100% sensitivity, 73% specificityWada: 92% sensitivity, 45% specificity
Binder et al., 2008 Epilepsia
Page 33
Memory outcomes with fMRI
44 TLE patients (24 LTLE)
Covert verb generation task (letter – word task)
Stronger pre-resection L frontal activation in LTLE -> greater post-resection naming decline naming
Stronger activation in R after resection -> better naming performance
Bonelli et al., 2012 Epilepsia Page 34
Memory outcomes with fMRI
50 TLE patients (23 L); memory encoding task
Covert memorization of presented concrete nouns
Stronger pre-resection L frontal and ATL activation in LTLE -> greater post-resection verbal memory decline
Bilateral posterior hippocampal activation -> less post-resection verbal memory decline
Sidhu et al., 2015 Neurology
Page 35
FMRI Summary – What is missing?
Studies of fMRI’s ability to predict language and memory outcomes in various surgical treatments (ATL vs. amygdalo-hippocampectomy vs. laser ablation)
Comparisons of various fMRI language and memory tasks in regard to their ability to lateralize functions, their level of agreement with IAP, and their ability to predict postsurgical outcomes
Comparisons of various fMRI analysis methods
Multicenter replicability studies
Studies of patients with E-TLE and lesional epilepsy
Studies specifically targeting pediatric epilepsy population
Page 36Binder et al., 2011, NeuroImage
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Page 37
Why simultaneous EEG and fMRI?
Understanding mechanisms and significance of rhythms and spontaneous brain activity
Health (e.g., alpha rhythm, sleep waves)
Evoked potentials (health and disease)
Localization of abnormal activity (SWD)
Presurgical evaluation
Planning of the extent of surgical resection
Page 38
Estimated/standard hemodynamic response curve of BOLD signal
Hawco et al., 2007 NI, de Munck et al., 2007 NI, Szaflarski et al., 2010 EB
Page 39Bai et al., 2010 J Neuroscience Page 40Szaflarski et al., 2013 Epilepsia
Page 41
EEG combined with fMRI (EEG/fMRI)
In Idiopathic Generalized Epilepsies
Cortical BOLD signal changes typically occur before the thalamic changes
There is directionality of signal flow from cortex to thalamus
There is beginning evidence that different thalamic nuclei are involved in different way in GSWD generation and maintenance
GSWDs have affect resting state
fMRI can be used to constrain source localization
Applicable to focal onset seizures
Page 42
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Page 43
EEG/fMRI and surgical outcomes
Non-lesional FLE – in 2/2 operated patients EEG/fMRI correlated with previously not visualized cortical abnormalities
6/7 seizure-free patients BOLD signal was concordant with area of resection (3/4 not-seizure-free BOLD signal outside of resection area)
In 35 patients surgical outcome correlated with the degree of overlap between EEG/fMRI BOLD changes and surgical resection
In 4/8 previously denied surgical treatment EEG/fMRI provided complimentary information that resulted in IC monitoring
Moeller et al., 2009 Neurology, Thornton et al., 2010 JNNP, An et al., 2013 Epilepsia Page 44
EEG/fMRI Summary - What is missing?
Unified data collection and analysis methods
Prospective studies of non-lesional (MRI(-)) patients
Randomized studies assessing the contributions of fMRI to the surgical decision-making
Randomized studies assessing the issue of BOLD signal area resection
Page 45
Today
Churchland et al. 2014, Nature Page 46
One day in the future
Sequence development
Data processing and merging
Hybrid systems
Higher field
Portability
Therapy delivery
Page 47
Sequences
Improved MR sequences will result in spatial resolution closer to histology HR-MICRA
Gadolinium and oxide nanoparticles
Chemical imaging Neuro-inflammation
BBB
GluCEST (glutamate chemical exchange saturation transfer)
Structural imaging as an early predictor of outcome of medical vs. surgical therapies
Davis et al., 2016, Sci Transl Med
Page 48
Data processing and merging
Machine learning algorithms to personalize diagnosis and outcome predictions Merging with genetics and neuropsychology
Subjective interpretation supplemented with or replaced by personalized tools
Connectivity analyses and connectomics Connectomics predicted outcomes in TLE (Bonilha et al., 2015,
Neurology; Keller et al., 2016, Brain)
Understanding of structural and functional network redundancy and connectivity will allow treatment via modifying nodes remote to the ictal onset zone
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Page 49
Hybrid systems
Hybrid MEG/MRI Feasibility?
MEG signal: 10-15T – 12-14 orders of magnitude lower than MRI field
Hybrid PET/MRI Utility?
Improvements in sub-millimeter imaging may result in additional implementation
Hybrid SPECT/MRI Utility?
Mainly animal research
VEP maps withECD projections
Vesanen et al., 2013, MRM Page 50
Higher field
7T Systems
E.g., Siemens 7T Magnetom Terra or Philips 7T Achieva Goal of improving SNR
Better contrast and smaller voxel size
Better metabolic imaging
Higher field for research and clinical applications
8T, 9.4T or higher?
Better metabolic imaging?
Page 51
Portability AM-PET (ambulatory micro-dose PET)
10% od standard dosage of radioisotope
Lightweight and motion-tolerant
In epilepsy
Ictal AM-PET FDG
5-HT1A
GABAA (Flumazenil)
CB1
Opioid
nAChR
Courtesy of Julie Brefczynski-Lewis, PhD
Wearable MRIwww.Nano-Tera.ch
Page 52
Therapy delivery
MRI-guided therapy
Therapeutics (e.g., AEDs) or “cytotoxic agents” conjugated to e.g., iron oxide nanoparticles and targeting ligands
Binding receptors to cells important for seizure initiation
MRI-guided release of agents to modulate or destroy targeted cells (magnetized nanoparticles)
Page 53
THANK YOU
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Current and Future Trends in Development of Antiepileptic Drugs
Henrik Klitgaard, Ph.D.Vice President, Fellow, Neuroscience Research
UCB Pharma
Disclosure
Henrik Klitgaard is an employee of UCB Pharma
This presentation is not accredited for CME credit.
2
Learning Objectives
• Inform on discovery approach leading to the existing armamentarium of AEDs
• Detail screening approach and key pharmacology for current focus on discovery of new AEDs for treatment of sub‐populations with drug refractory epilepsy
• Describe preclinical models, emerging biology and biomarkers for future identification and translation of antiepileptogenictreatments
• Address perspectives for future innovation in AED development
3
Significant number of AEDs available for epilepsytreatment
RetigabinePerampanel
Brivaracetam
Adapted from Löscher and Schmidt ‐ Epilepsia 2011; 52:657‐78
4
Majority of AEDs discovered by seizure protection in MES and PTZ tests
Phenytoin (1937)
Pentylenetetrazol
Trimethadione (1944)
MES PTZ
Klitgaard et al. ‐ In Animal and Translational Models of Behavioral Disorders. Volume 2. McArthur RA & Borsini F (Eds.), Elsevier, NY, pp 311–35, 2008
5
The availability of the MES test was a revolution
Adapted from Löscher and Schmidt ‐ Epilepsia 2011; 52:657‐78
RetigabinePerampanel
Brivaracetam
AfterMES
Before MES
6
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And improved treatment of epilepsy – residual innovation
• More treatment options
• Improved tolerability and safety profile
• Lower risk of drug‐drug interactions
Löscher et al. ‐ Nature Review Drug Discovery 2013, 12:757‐776
7
But current AEDs focus on reductionistic and neurocentric concept of excitation/inhibition balance
EXCITATION INCREASE
SEIZURE
INHIBITION DECREASE
SEIZURE
Na+ channel antagonistsCa2+ channel antagonistsAMPA receptor antagonists GABAA agonists
Enhance GABA levels
Margineanu and Klitgaard ‐ Expert Opinion Drug Discovery; 2009; 4(1):23‐32
8
Prior incentives for AED development has disappeared
placebo response of add‐on POS trials
Risk/benefit tolerance regulatory requirements and class labelling
Differentiation impact on pricing
Generics competition
Attrition
Löscher et al. ‐ Nature Review Drug Discovery 2013, 12:757‐776
9
Serious unmet medical need remains
Löscher et al. ‐ Nature Review Drug Discovery 2013, 12:757‐776
• Drug refractory epilepsy
• Comorbidities
• Absence of treatments that prevent epilepsy or
alter the course of the disease
10
The ASP at NIH was instrumental to maximize the drugdiscovery potential of the MES test
RetigabinePerampanel
Brivaracetam
Adapted from Löscher and Schmidt ‐ Epilepsia 2011; 52:657‐78
11
Pharmacoresistance Epilepsy Workflow for ETSP
Courtesy from Dr. John Kehne, Ph.D., Program Director, Epilepsy Therapy Screening Project (ETSP), NIH
12
Acute Seizure Models • 6 Hz Electrical Stimulation (m,r)• Maximal Electroshock Test (m,r)
Behavioral Toxicity Screens• Rotarod (m)• Neurological Impairment (r)• Locomotor Activity (r)
Chronic Seizure Models• Corneal Kindled Seizure Test (m)• Spontaneous Bursting Slice from
Post‐kainate Status Epilepticus Rat (in vitro)
Mesial Temporal Lobe Epilepsy Model (m)
Lamotrigine‐Resistant Amygdala Kindling (r)
Post‐Kainate Status Epilepticus‐Induced
Spontaneous Recurrent Seizures (r)
Video‐EEG monitoring
IDENTIFICATION DIFFERENTIATION
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New pharmacology target pharmacoresistance:mTOR pathway
13
Meng et al. – J. Neurol. Sci. 2013; 332:4‐15
New pharmacology target pharmacoresistance: cannabinoids
14
Adapted from Ibeas Bih et al. – Neurotherapeutics 2015; 12:699‐730
10
10
13
32
Receptor targets
Ion channel targets
Transporter targets
Enzyme targets
New pharmacology target pharmacoresistance: neurosteroids
15
Reddy and Estes – Trends Pharmacol. Sci. 2016; 37(7):543‐561
New pharmacology target pharmacoresistance: pre‐ and post‐synaptic inhibition
16
Recent explosion of genetic discoveries in epileptic encephalopathies may enable precision medicine
0
5
10
15
20
25
30
35
40
45
50
2002 2004 2005 2008 2009 2010 2012 2013 2014
• Exponential growth with recent sequencing technologies
• GRIN2A → Memantine
• KCNT1 → Quinidine
Courtesy of Dr Jonathan Van Eyll, UCB
17
# of genesidentified
New pharmacology and gene discovery now permit to target sub‐populations with refractory epilepsy –dominant innovation
Löscher et al. ‐ Nature Review Drug Discovery 2013, 12:757‐776
BLOCKBUSTER MODEL
Large clinical trials Tailor-made drugs
SUB‐POPULATIONS
MINI BUSTER MODEL
18
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Serious unmet medical need remains
Löscher et al. ‐ Nature Review Drug Discovery 2013, 12:757‐776
• Drug refractory epilepsy
• Comorbidities
• Absence of treatments that prevent epilepsy or
alter the course of the disease
19
Strong platform of animal models for epileptogenesisresearch
Developmental alterations
Kindling acquisition
Latent period
Latent period
Genetic models
TRIGGERING EVENT EPILEPTOGENESIS EPILEPSY
Disease modifying therapy
Antiepileptogenictherapy
Significant reduction
in seizure threshold /
spontaneous seizures
Fully kindled
Spontaneous seizures
Spontaneous seizures
Birth
Initiation of chronic stimulation
Initiate and terminate SE
Traumatic Brain Injury
Kindling models
Status epilepticusmodels
Insult specific models
Simonato et al. ‐ Epilepsia 2012; 53(11):1860‐7
20
New biology reveal promising antiepileptogenicproperties in preclinical models – emergent innovation
Löscher et al. ‐ Nature Review Drug Discovery 2013, 12:757‐776
21
New biology with antiepileptogenic potential: microRNAs
22
mRNA degradation
Translational repression
• miRNAs bind via imperfect complementary base pairing to 3’UTR of messenger RNAs resulting in
translational repression
• A single miRNA can bind and regulate multiple different mRNAs
• miRNAs cause blockage of networks and pathways rather than single gene inhibition
From Castanotto et al. ‐ Nature 2009; 457(7228):426‐33
Silencing microRNA‐134 produces neuroprotectiveand prolonged seizure‐suppressive effects
23
Jimenez‐Matheos et al. – Nature Medicine 2012; 18(7): 1087‐1094Scr: scrambled sequenceAnt: antagomer
Prevention of epilepsy and anxiety: TrkB kinase
Chemical‐genetic approach
TrkB sensitive to inhibition by 1NMPP1.
1NMPP1
Chen et al. ‐ Neuron 2005; 46(1):13‐21
24
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Prevention of epilepsy and anxiety: TrkB kinase
Liu et al. ‐ Neuron 2013; 79:31‐38
25
Serious unmet medical need remains
Löscher et al. ‐ Nature Review Drug Discovery 2013, 12:757‐776
• Drug refractory epilepsy
• Comorbidities
• Absence of treatments that prevent epilepsy or
alter the course of the disease
26
Attrition will be a major challenge for successful translation of emergent innovation
26.1%
19.1%17.1% 16.3% 15.3% 15.1% 14.7%
13.2% 12.8%11.4% 11.1%
9.6%8.4%
6.6% 6.2%5.1%
0%
5%
10%
15%
20%
25%
30%
LOA from phase 1
Likelihood of approval (LOA) from phase 1
Adapted from Bio Industry Analysis Report, Clinical Development Success Rates 2006–2015, June, 2016
27
Failure
Lack of efficacy is primary reason for attrition during clinical development
Adapted from Bio Industry Analysis Report, Clinical Development Success Rates 2006–2015, June, 2016
63.2%
30.7%
58.1%
85.3%
9.6%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Phase 1 tophase 2
Phase 2 tophase 3
Phase 3 toNDA/BLA
NDA/BLA toapproval
Phase 1 toapproval
Probab
ility of success
Probability of success
All diseases
28
Minimal attrition of previous AED development facilitated by predictable animal models
Adapted from Bio Industry Analysis Report, Clinical Development Success Rates 2006–2015, June, 2016
Probability of success
All diseases
63.2%
30.7%
58.1%
85.3%
9.6%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Phase 1 tophase 2
Phase 2 tophase 3
Phase 3 toNDA/BLA
NDA/BLA toapproval
Phase 1 toapproval
Probab
ility of success
EPILEPSY
70%
29
Reduce attrition by optimal design of preclinical studies
Important parameters to control:
• Choice of species, strains and age of animals
• Methodology for in vivo seizure initiation, termination, recording and typing
• Determine PK/PD relationship
• Sample size to reflect purpose of experiment
• YES/NO (limited sample size)
• SUPERIOR/INFERIOR vs placebo/comparator (randomized, blinded and potentially multicenter approach)
Important parameters for conclusions:
• Therapeutic gain – to be assessed by impact on both seizure and behavioral recordings and biological processes of the target
• Determine therapeutic treatment window and duration of treatment effect
• Establish therapeutic index based on tolerability and safety measures
30
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Reduce attrition by biomarkers that permit patient stratification
Adapted from Bio Industry Analysis Report, Clinical Development Success Rates 2006–2015, June, 2016
63%
28%
55%
83%
8.4%
76%
46%
76%
94%
25.9%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Phase 1 tophase 2
Phase 2 tophase 3
Phase 3 toNDA/BLA
NDA/BLA toapproval
Phase 1 toapproval
Pro
bab
ility
of
succ
ess
Without biomarkers With selection biomarkers
Probability of success
With or without selection biomarkers
31
Biomarker discovery – progress but still lacking validation and clinical translation
32
• Genome‐wide association studies reveal possible associations between genetic variants and epilepsy
• Dysregulation of miRNA observed in surgical specimens and plasma from epilepsy patients
• MRI studies associate structural changes and damage with epilepsy
• Invasive EEG identify high‐frequency oscillations as an interictal marker of epileptogenic zones
• Imaging techniques visualize neuroinflammation and microvascularinjury, associated with epilepsy
Pitkänen et al. ‐ Lancet Neurol 2016; 15: 843‐856
Reduce attrition by combination therapy with approved drugs targeting different epileptogenic processes?
33
Proposal by Dr. Pavel Klein; Hunt et al. ‐ Front. Cell. Neurosci; 2013; Jun 18;7:89. doi: 10.3389/fncel.2013.00089
Current and Future Trends in Development of AEDs ‐2016
Residual innovation:
• Screening in seizure tests have identified most of the current AEDs
Dominant innovation:
• New pharmacology and gene discovery now permit to target sub-populations with refractory epilepsy – a 4th generation of AEDs is coming!
Emergent innovation:
• Several antiepileptogenic mechanisms identified in preclinical models
• Some of these inhibit development of both seizures and psychiatric comorbidities
• Minimize attrition of translation by optimal design of preclinical studies, biomarkers and combination therapy
34
Future trends in the development of AEDs – two wild cards
35
CRISPR – gene editing
36
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Advances in device technologies will result in paradigm shift from chronic to acute AED treatment?
37
Kim et al. ‐ Science Advances 2016; 2:e1600418
Materials and engineering advances create an opportunity to shift from periodic clinical visits to continuous monitoring (e.g. non‐invasive physiologic signal sensors)
Portable, predictive analytics create an opportunity to shift from chronic, systemic medication usage to intermittent, targeted administration “as needed” in periods of high risk.
Current and Future Trends in Development of AEDs ‐2031
Residual innovation:
• A new, marketed generation of “mini-buster” AEDs that target specific sub-populations with refractory epilepsy
• Precision medicine an established and beneficial approach
Dominant innovation:
• Advances in genetic and biomarker research and in processing of big data permit clinical development projects to be associated with a diagnostic and target specific etiologies
• Antiepileptogenic and disease modifying drug candidates under clinical development
Emergent innovation:
• Advances in disease understanding of autoimmune diseases permit curative treatment of autoimmune epilepsy
• Impact of device(s) enabling seizure prediction permit acute treatment of chronic epilepsy
38
Future trends: towards 4 and 5 generation AEDs!
Adapted from Löscher and Schmidt ‐ Epilepsia 2011; 52:657‐78
RetigabinePerampanel
Brivaracetam
1st generation
2nd generation
3rd generation
39
Future trends: towards 4 and 5 generation AEDs!
Adapted from Löscher and Schmidt ‐ Epilepsia 2011; 52:657‐78Adapted from Löscher and Schmidt ‐ Epilepsia 2011; 52:657‐78
RetigabinePerampanel
Brivaracetam
1st generation
2nd generation
3rd generation
2020 2030 2040
4th generation
AEDs that targetspecific sub‐
populations with drugrefractory epilepsy
AEDs that targetspecific sub‐
populations with drugrefractory epilepsy
5th generation
. AEDs with a diagnostic that target specificetiologies. Antiepileptogenic and disease modifying drugs. Acute treatment of chronic epilepsy
. AEDs with a diagnostic that target specificetiologies. Antiepileptogenic and disease modifying drugs. Acute treatment of chronic epilepsy
#AES2016
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Epilepsy Genetics and Cell Signaling Pathways:
A Futurists ViewPeter B. Crino M.D., Ph.D.
Professor and ChairDepartment of Neurology
University of Maryland School of Medcine
Disclosure
•R01NS082343-01•R21NS087181-01•EUREKA•STTRSAB and Inventor, Evogen Inc.UPN-X5727C1U.S.A/U.S. Patent Application No. 14/943,101 Provisional patent applications 62/274,551 and 62/274,578 (January 2016)
Learning Objectives
• To define how gene sequencing will aid with epilepsy diagnosis and treatment
• To define how identification of cell signaling pathway alterations will affect treatment options
“Futures cannot be predicted, but futures can be invented.”-Dennis Gabor, 1971 Nobel Prize in Physics, invention of holograms
What SHOULD happen, not necessarily what WILL happen….
mTOR Signaling Nodes 2001
NUCLEUS
CYTOPLASM
TSC1
TSC2
S6
eIF4E
Rapamycin
mTORC1
S6K1
mTOR
raptor
P
P
P
P
4E‐BP1
Akt
PDK1
PI3KIRS
EXTRACELLULAR SPACE
P
P
IGF1EGFHGF
mTOR Function in brain??
AMP/ATP
Lysosome
CYTOPLASM
TSC1
TSC2
S6
eIF4E
AMPK
Rapamycin
mTORC1
S6K1
MO25
STRAD
LKB1
mTOR
raptor
PP
P
P
P
P
P
4E‐BP1
Akt
PDK1PTEN
PI3KIRS
EXTRACELLULAR SPACE
P
P
NPRL2
P
ACC
P
REDD1
DEPTOR
TBC1D7
IGF1EGF
B‐RAF
O2
HGF
STAT3
VEGF
A.A.
DEPDC5
Cell SizeCell Migration
Stem Cell DifferentiationDendrite Outgrowth
Axon OutgrowthDendritic protein syntesisSynaptic plasticity -LTP
GATOR1GATOR1
mTOR Signaling Nodes 2016
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Future Genome and Signalome Strategies
DiagnosticsPrognosticsDiscoveryPreventionTargeted Therapeutics
Twenty‐five Years ago….
NO…….High-throughput gene sequencingMassively parallel signature sequencingDNA Arrays/target/panel/platformshRNA/GFP/CRISPRAnd….Numerous epilepsy genes were unknownCould we have predicted this?
Future Genome and Signalome Strategies
Change the Landscape for……‐Diagnostics‐Prognostics‐Discovery‐Prevention‐Targeted Therapeutics
All Human Epilepsy Genes Will Be Known and Full Variant Maps Will Be Available - Germline
“Epilome”“Ictome”“Fitome”“Focal Dyscognitome”
Monogenic causesSyndromic links
AutosomalX-linkedMitochondrial
Ethnic VariantsSex Variants
Causative Variants
ALL patients will have full exome screening
‐Inexpensive
‐Rapid turnaround (hours)
‐Available to ALL individuals‐no fiscal, geographic, regulatory barriers
Blood, saliva or buccal?
Single Cell SequencingGawad et al., 2016
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3
All Causative Variants Will Be MappedAt presentation:-all patient exomes are screened-Pathogenic variants identified-Computational “GO” analysis for protein targets-Computational pharmacopaiea analyzed-Best fit for patient-Clinical implementation and therapy
Use of Variants for Early identification and Prediction: Precision Medicine - SUDEP
At presentation:-all patients screened-variants detected-predictive algorithms-actionable preventions-AICD/pacemaker, drugs
SUDEP eradicated
Causative Variants
New Genomics: Rheostatic Susceptibility for Seizures and Epilepsy
ACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTG
ACTGACTGACTGACTGAGTGACTGACTGACTTACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTTACTGACTGACTGACTGACTGACTGACTG
ACTGAATGACTGACTGGCTGACTGACTGACTTACTGACTGACTGACTGACTGACTGACTGACTGAATGACTGACTGGCTGACTGACTGACTTACTGACTGACTGACTGACTGACTGACTG
LOW
MEDIUM
HIGH
ACTGAATGACTGACTGGCTGACTGACTGACTTACTGACTGACTGACTGACTCACTGACTGACTGAATGACTGACTGGCTGACTGACTGACTTACTGACTGACTGACTGACTCACTGACTG
ACTGACTGACTGACTGAGTGACTGACTGACTGACTCACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTCACTGACTGACTGACTGACTGACTG
Rheostatic Susceptibility for Seizures and Epilepsyand Co‐Variation with Known Epilepsy Genes
ACTGACTGACTGACTGAGTGACTGACTGACTTACTCACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTTACTCACTGACTGACTGACTGACTGACTG
ACTGAATGACTGACTGGCTGACTGACTGACTTACTCACTGACTGACTGACTGACTGACTGACTGAATGACTGACTGGCTGACTGACTGACTTACTCACTGACTGACTGACTGACTGACTG
LOW
MEDIUM
HIGH
PleotropyGenotype‐Phenotype
ACTGAATGACTGACTGGCTGACTGACTGACTTACTCACTGACTGACTGACTCACTGACTGACTGAATGACTGACTGGCTGACTGACTGACTTACTCACTGACTGACTGACTCACTGACTG
Rheostatic Analysis Will Require Massive Parallel Bioinformatics
ACTGACTGCCTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGTCTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACGGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACAGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGAGTGACTGACTGACTGACTGACTGACTGACCGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTCACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAATGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTG ACTTACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTG
Epistasis and Gene Modifiers Will Be Defined
At presentation:‐all patients screened‐variants detected‐predictive algorithms‐actionable preventions‐AICD/pacemaker, drugs
SUDEP eradicated
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All Human Epilepsy Genes Will Be Known and Full Variant Maps Will Be Available ‐ Somatic
“Epilome”“Ictome”“Fitome”“Focal Dyscognitome”
Monogenic causesSyndromic links
Extreme High Depth Sequencing‐detect somatic variants in blood
Ethnic VariantsSex Variants
iPSC Based Advanced Human Stem Cell Modeling of All Epilepsy Gene Mutations in All Types of Neurons
Gene Editing Tools for Mutation Correction in Isogenic Cell Lines – Test Rescue Effect
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas (CRISPR‐associated) system, TALENs (Transcription activator‐like effector nucleases), ZFNs (Zinc finger nucleases)
Ongoing Somatic Mutagenesis in BrainContributes to Epilepsy Susceptibility
Somatic mutations in:‐dentate gyrus progenitor cells‐SVZ progenitor cells‐reactive astrocytes‐pericytes‐microglia‐Confers differential susceptibility or resistance
Highly dynamic mutational landscape
Pharmacogenomics
Predictive Landscape for Drug Responsiveness-beyond HLA typing
Predictive Landscape for Drug Resistance
Predictive Landscape for Drug Adverse Effects-Allergic reactions i.e., angioedema, respiratory failure, TEN-Sedation
Predictive Landscape for Drug Teratogenicity
Mouse Models for Epilepsy Blood sample from patient
High depth whole exome/genome sequencing
Mutation identification
Mouse Model engineered with human mutation-knockdown, knockout, overexpression are obsolete-ES cell bank for all known variants
Identification of variants-modifiers-epistasis-critical, relevant, unknown
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Polygenic inheritance of susceptibility and resistance to cancer in mouse models.
Tommaso A. Dragani Cancer Res 2003;63:3011-3018
©2003 by American Association for Cancer Research
Epileptogenesis
Use of Mouse Models – with modifier loci
Mouse engineered with human mutation
Identification of known human variants‐modifiers‐epistasis
Mouse Model engineered with human mutation‐knockdown, knockout, overexpression are obsolete‐ES cell bank for all known variants
Differential Mouse models
It Should Be Very Interesting…….
#AES2016